The peritoneal cavity has been a convenient anatomic compartment for the study of macrophages for decades. This is due to the ease of retrieving cells from the peritoneal lavage and that macrophages are a dominant population in this lavage in steady state conditions and in many inflammatory states. However, in light of the vast diversity between macrophages from different organs, the peritoneal macrophage should no longer be viewed as simply a model macrophage. The transcription factor Gata6 is critical in governing the lifecycle of resident peritoneal macrophages as well as those in the pleural cavity, but not in other macrophages. We began to consider what functional consequences might emerge in mice lacking a major portion of their peritoneal macrophages due to Gata6 deficiency. Exciting preliminary data have emerged which suggest that beyond defending the peritoneal compartment itself, resident peritoneal macrophages have the capacity to defend other organs within the visceral cavity. Injury to the colon leads to the recruitment of macrophages that express a host of markers only observed in resident peritoneal macrophages (Gata6, CD93, ICAM-2). When mice with a reduced peritoneal macrophage compartment receive colonic injuries, healing is impaired. A hypothesis thus emerges that a way for resident peritoneal macrophages to defend the peritoneum is to also defend the organs whose integrity must be maintained in order to protect the peritoneum. Indeed, the defense of the intestine by peritoneal macrophages might be so robust as to involve their direct recruitment to intestine along the serosal surface. An appealing aspect of this model is that it might account for puzzling phenomena known for some time but not explained. In the phenomenon of the macrophage disappearance reaction, in which inflammation-triggered resident peritoneal macrophages disappear from the peritoneal cavity, the observations in the injury model above cause us to postulate that a major peritoneal macrophage relocation occurs to the intestine and perhaps at the borders of other organs. Secondly, in H. polygyrus infection of the intestine, it is known that resident peritoneal macrophages expand in numbers without further inflammation and this expanded pool of macrophages becomes polarized to an alternatively activated state. Questions arise like why does the peritoneal macrophage pool respond when the parasite is confined to the intestine? And how do the resident peritoneal macrophages even know there has been a change of status in the intestine? It seems as though the events in the intestine are able to influence the peritoneal macrophage pool. The latter question raises an extension to our hypothesis that peritoneal macrophages might act to defend the intestine with the additional concept that there may be two-way crosstalk between the intestine and peritoneal cavity. That is, our overarching hypothesis is that intestinal activities shape the unique identity of peritonea macrophages that they in turn participate in intestinal defense. Macrophages in the pleural cavity appear identical to those in the peritoneum, so this work may in the future extend to how pleural macrophages impact responses in the lung.